SYDNEY, Australia—Serum levels of the transforming growth factor ß superfamily member macrophage inhibitory cytokine 1 (MIC-1) may help identify rheumatoid arthritis (RA) patients who are at the greatest risk for developing erosive disease and need aggressive therapy, thus enabling clinicians to spare less high-risk patients unnecessary treatment and attendant toxicity, according to a study in the March issue of Arthritis & Rheumatism.1 MIC-1 expression is also upregulated in several kinds of cancer, is a strong predictor of disease dissemination in prostate cancer, and is an independent predictor of atherosclerotic events.

"Depending on the cut-off used, 100% of patients who have erosive disease can be identified, I am not aware of any test available that has this potential." —Samuel N. Breit, MBBS, MD, FRACP, FRCPA.
"A major reason for early aggressive treatment of RA is the prevention of joint destruction. However, about a quarter of patients with RA never develop erosions," study author Samuel N. Breit, MBBS, MD, FRACP, FRCPA, told CIAOMed. Dr. Breit is professor of medicine and head of the Inflammation Research Group with the Centre For Immunology at St. Vincent's Hospital and University of New South Wales, in Sydney, Australia.

"The identification of this subgroup, using the erosive disease score and severity score algorithms, would allow them to be treated far less aggressively. This approach could significantly reduce treatment-associated side effects. Validation of algorithms including MIC-1 for the prediction of response to autologous bone marrow transplant has the capacity to drastically reduce treatment-associated morbidity and mortality by identifying patients who are unlikely to respond to this therapy."

Researchers compared MIC-1 levels in mild RA, severe RA, and nonRA controls

Lead author David A. Brown, PhD, FRACP, also at St. Vincent's Hospital and University of New South Wales, and colleagues recruited 91 RA patients. Serum was collected from 83 patients and synovial biospsy samples from the remaining eight patients. The investigators examined MIC-1 levels in 61 RA outpatients considered to have nonsevere RA, in 22 RA patients with severe, treatment-resistant RA who subsequently had hematopoietic stem cell transplantation (HSCT), and in 260 control serum donors.

Serum levels of MIC-1 were higher in RA patients than in controls and reflected RA disease severity independently of classic disease markers.

MIC-1 was also detected in rheumatoid synovial specimens, but there were too few patients to determine whether MIC-1 expression was increased in RA synovium. However, the researchers found that an allelic variation of MIC-1 was associated with earlier erosive disease and severe treatment-resistant chronic RA. Multivariate logistic regression identified increased serum levels of MIC-1, shorter disease duration, younger age at disease onset, and lower serum levels of C-reactive protein as independent predictors of joint erosion.

New algorithm with MIC-1 could reduce treatment-associated morbidity and mortality

Algorithms that included serum and/or allelic variation in MIC-1 were constructed. The investigators report that the new algorithms predicted the presence of severe disease, joint erosions, and response to HSCT.

The erosive disease score including MIC-1 had an area under the curve of .924. "Depending on the cut-off used, 100% of patients who have erosive disease can be identified," Dr. Breit said. "I am not aware of any test available that has this potential."

The researchers note, "In a theoretical population of 1 million patients with RA with a prevalence of erosive disease of 75%, 9.2% of patients could be identified for assignment to less aggressive therapy."

MIC-1 versus anti-CCP

Other disease markers, such as anti-citrullinated protein (anti-CCP) antibody titre, have also been investigated for their effectiveness in predicting erosions in RA but are inferior to MIC-1, Dr. Breit told CIAOMed. "While there is clearly an association between anti-CCP titre and RA severity and erosions and anti-CCP has a 98% specificity for the diagnosis of RA, anti-CCP is not that sensitive, as there are a significant number of patients who are anti-CCP negative."

MIC-1 is detectable in the serum of all RA patients, Dr. Breit said, and might be more suitable for the prediction of erosive disease, but there have been no direct comparisons between MIC-1 and anti-CCP.

Reference

1. Brown DA, Moore J, Johnen H, et al. Serum macrophage inhibitory cytokine 1 in rheumatoid arthritis: a potential marker for erosive joint destruction. Arthritis Rheum. 2007;56:753-764.